Marihuana use and abuse continues to be a significant social problem. In addition, some therapeutic utility for marihuana derivatives is probable. Our broad objective is to develop and test hypotheses regarding the sites and mechanisms of action of cannabinoids in the central nervous system. We propose to integrate biochemical, behavioral and neurophysiological data that relate to the hypotensive and hypothermic actions of the cannabinoids. Such information will contribute to a better understanding of the mechanisms involved in the actions of this class of pharmacological agents.. We will perform biochemical studies to determine whether or not the THCs have a primary effect on neurotransmitter mechanisms within the central nervous system. Specifically, we will examine the effect of THC on noradrenergic presynaptic autoreceptors utilizing synaptosomal synthesis techniques. We will also examine the relationships between THC and Beta-receptors, alpha-adrenergic receptors, dopamine receptors and serotonin receptors using a variety of biochemical techniques. Neurophysiological studies in cats will be used to test the hypothesis that the THCs have a dual action on central cardiovascular mechanisms. These agents appear to antagonize inhibitory cardiovascular mechanisms from higher centers. The balance between these two mechanisms will determine whether one observes an initial increase in sympathetic outflow which is caused by antagonism of the inhibitory effects from higher centers upon the basal motoneurons or a decrease in heart rate and blood pressure which may result from a direct action of the THCs upon the basal motoneurons to decrease sympathetic outflow. Additional studies are described in which thermosensitive neurons have been localized in several areas of the central nervous system. We will attempt to characterize the effects of both active and inactive TCs upon these neurons. We will characterize the neurophysiological mechanisms involved in THC induced respiratory depression. Finally, we will attempt to integrate the biochemical and neurophysiological mechanisms studied in the cat.